Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides

ABSTRACT

The invention relates to new substituted imidazoles of general formula 
                         
wherein R 1  to R 3  and X are defined as claims, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, and processes for preparing them and their use as intermediates for preparing pharmaceutical compositions or pesticides.

The present invention relates to new substituted imidazoles of general formula

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof and processes for the preparation thereof. The compounds may be used as intermediates for preparing pharmaceutical compositions or pesticides. Starting from them, other heterocyclic rings may be linked to the imidazole to form important polycyclic basic structures. They are particularly suitable for preparing imidazo[4,5-d]pyridazin-4-ones and imidazo[4,5-c]pyridine-4-ones which may be used, e.g., as DPP IV inhibitors in the treatment of diabetes (cf., e.g., WO 03/104229). Moreover, a broad range of substitutions may be carried out at three positions of the imidazole under different reaction conditions, making these compounds particularly attractive as the scaffold in building up libraries of combinations.

In the above formula I

-   R¹ denotes a fluorine, chlorine, bromine, or iodine atom, -   R² denotes a C₃₋₈-alkyl group, -   a C₁₋₃-alkyl group substituted by a group R_(a), while -   R_(a) denotes a C₃₋₇-cycloalkyl group optionally substituted by one     or two C₁₋₃-alkyl groups, -   a C₃₋₈-cycloalkenyl group optionally substituted by one or two     C₁₋₃-alkyl groups, -   an aryl group or -   a heteroaryl group, -   a C₃₋₈-alkenyl group, -   a C₃₋₆-alkenyl group substituted by a fluorine, chlorine or bromine     atom or by a trifluoromethyl group, -   a C₃₋₈-alkynyl group, -   an aryl group or -   an aryl-C₂₋₄-alkenyl group, -   X denotes an oxygen or sulphur atom or -   a nitrogen atom which is substituted by R_(b), while -   R_(b) denotes a hydrogen atom, -   a hydroxy, aryloxy, arylmethyloxy, heteroaryloxy,     heteroarylmethyloxy or C₁₋₁₀-alkyloxy group, while the hydrogen     atoms of the alkyloxy group may be wholly or partly replaced by     fluorine atoms, -   a C₁₋₁₀-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,     C₁₋₁₀-alkyloxy-carbonyl, C₁₋₁₀-alkylaminocarbonyl,     di-(C₁₋₁₀-alkyl)-aminocarbonyl, C₁₋₁₀-alkylsulphonyl, arylsulphonyl,     heteroarylsulphonyl, C₁₋₁₀-alkylsulphinyl, arylsulphinyl or     heteroarylsulphinyl group, while the hydrogen atoms of the     above-mentioned C₁₋₁₀-alkyl groups may be wholly or partly replaced     by fluorine atoms, -   a C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₇-cycloalkyl or     C₅₋₈-cycloalkenyl group, while the hydrogen atoms in the     above-mentioned groups may each be wholly or partly replaced by     fluorine atoms and in the above-mentioned groups 1 to 4 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   an aryl group or -   a heteroaryl group, -   or -   R_(b) and R³ are linked together and are closed up into a ring at     the nitrogen atom, while R_(b) and R³ together denote -   a C₂₋₇-alkylene group, while one or two methylene groups may each be     substituted by one or two fluorine atoms or replaced by an oxygen or     sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl,     sulphinyl or sulphonyl group, -   or a C₄₋₇-alkenylene group, while one or two methylene groups may     each be substituted by one or two fluorine atoms or replaced by an     oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a     carbonyl, sulphinyl or sulphonyl group and the double bond may be     part of an aryl or heteroaryl group anellated to the ring, -   and -   R³ denotes a hydrogen atom, -   a C₁₋₂₀-alkyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₁₋₁₂-alkyl group substituted by a group R_(c) wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms     and wherein 1 to 4 methylene groups may each be replaced by an     oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a     carbonyl, sulphinyl or sulphonyl group, while -   R_(c) denotes a C₃₋₁₈-cycloalkyl group optionally substituted by one     or two C₁₋₃-alkyl groups wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein one to two methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₅₋₁₈-cycloalkenyl optionally substituted by one or two C₁₋₃-alkyl     groups group wherein -   the hydrogen atoms may be wholly or partly replaced by fluorine     atoms, -   one to two methylene groups may each be replaced by an oxygen or     sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl,     sulphinyl or sulphonyl group and -   the double bond may be part of an aryl or heteroaryl group anellated     to the ring, -   an aryl group or -   a heteroaryl group, -   a C₃₋₁₈-cycloalkyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₃₋₂₀-alkenyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₅₋₂₀-cycloalkenyl group wherein the hydrogen atoms may be wholly     or partly replaced by fluorine atoms and wherein 1 to 4 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, and wherein the double bond may be part of an aryl or     heteroaryl group anellated to the ring, -   a C₃₋₂₀-alkynyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   an aryl group, -   a heteroaryl group, -   an aryl-C₂₋₆-alkenyl group -   or, if X does not represent a nitrogen atom which is substituted by     a hydroxy, aryloxy, arylmethyloxy, heteroaryloxy,     heteroarylmethyloxy or C₁₋₁₀-alkyloxy group, may also denote an     amino group which may be substituted by one or two C₁₋₃-alkyl     groups, -   or similarly, if X does not represent a nitrogen atom which is     substituted by a hydroxy, aryloxy, arylmethyloxy, heteroaryloxy,     heteroarylmethyloxy or C₁₋₁₀-alkyloxy group, may also denote a 3- to     7-membered cycloalkyleneimino group, while one to two methylene     groups of the cycloalkyleneimino group may each be replaced by an     oxygen atom or a carbonyl, sulphinyl or sulphonyl group, or -   R³ and X together represent a fluorine or chlorine atom, -   while by the aryl groups mentioned in the definition of the above     groups are meant phenyl or naphthyl groups which may be mono- to     pentasubstituted independently of one another by fluorine and     chlorine atoms and may be mono-, di- or trisubstituted by R_(d),     while the substituents may be identical or different and R_(d)     denotes a bromine or iodine atom, a trifluoromethyl, cyano, nitro,     amino, aminocarbonyl, aminosulphonyl, methylsulphonyl, acetylamino,     methylsulphonylamino, C₁₋₄-alkyl, C₁₋₃-alkyl-carbonyl, cyclopropyl,     ethenyl, ethynyl, hydroxy, C₁₋₄-alkyloxy, C₁₋₄-alkoxy-carbonyl,     methylsulphinyl, phenylsulphinyl, methylsulphonyl, phenylsulphonyl,     difluoromethoxy or trifluoromethoxy group, -   by the heteroaryl groups mentioned in the definition of the     above-mentioned groups are meant a pyrrolyl, furanyl, thienyl,     pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or     isoquinolinyl group -   or a pyrrolyl, furanyl, thienyl or pyridyl group wherein one or two     methyne groups are replaced by nitrogen atoms, -   or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or     isoquinolinyl group wherein one to three methyne groups are replaced     by nitrogen atoms, -   and the above-mentioned heteroaryl groups may be mono- to     pentasubstituted by fluorine and chlorine atoms and R_(d) may be     mono-, di- or trisubstituted, while the substituents may be     identical or different and R_(d) is as hereinbefore defined, -   by the cycloalkyl groups mentioned in the above definitions are     meant both mono- and polycyclic ring systems, which are either     bridged, spiro-bridged or anellated in construction, -   by the cycloalkenyl groups mentioned in the above definitions are     meant both mono- and polycyclic ring systems, which are either     bridged or anellated in construction, and have at least one C═C     double bond, -   while, unless otherwise stated, the above-mentioned alkyl, alkenyl     and alkynyl groups may be straight-chain or branched, -   with the exclusion of the compound wherein R¹ denotes a bromine     atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³     denotes a methyl group, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

Moreover, the saturated alkyl and alkyloxy moieties which contain more than 2 carbon atoms, mentioned in the definitions above and hereinafter, unless otherwise stated, also include the branched isomers thereof, such as, for example, the isopropyl, tert.butyl, isobutyl group etc.

Preferred compounds of general formula I are those wherein

-   R² and R³ are as hereinbefore defined, -   R¹ denotes a chlorine or bromine atom and -   X denotes an oxygen atom or an —NH— or —N(C₁₋₃-alkyl)-group, -   with the exclusion of the compound wherein R¹ denotes a bromine     atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³     denotes a methyl group, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

Particularly preferred are those compounds of general formula I wherein

-   R¹ denotes a chlorine or bromine atom, -   R² denotes a C₁₋₃-alkyl group substituted by a group R_(a), where     R_(a) is as hereinbefore defined, -   a C₃₋₈-alkenyl group, -   a C₃₋₆-alkenyl group substituted by a fluorine, chlorine or bromine     atom or by a trifluoromethyl group or -   a C₃₋₈-alkynyl group, -   X denotes an oxygen atom and -   R³ denotes a hydrogen atom, -   a C₁₋₂₀-alkyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₁₋₁₂-alkyl group substituted by a group R_(c) wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms     and wherein 1 to 4 methylene groups may each be replaced by an     oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a     carbonyl, sulphinyl or sulphonyl group, where R_(c) is as     hereinbefore defined, -   a C₃₋₈-cycloalkyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 4 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₃₋₂₀-alkenyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, -   a C₃₋₂₀-alkynyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom, by an —NH—     or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl     group, or -   an aryl-C₂₋₆-alkenyl group, -   with the exclusion of the compound wherein R¹ denotes a bromine     atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³     denotes a methyl group, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

Most particularly preferred are those compounds of general formula I wherein

-   R¹ denotes a chlorine or bromine atom, -   R² denotes a phenylmethyl group which may be substituted at the     phenyl ring by a fluorine, chlorine, bromine or iodine atom or by a     cyano or methoxy group, -   a C₃₋₈-alkenyl group, -   a C₃₋₈-cycloalkenylmethyl group, -   a C₃₋₆-alkenyl group substituted by a fluorine, chlorine or bromine     atom or by a trifluoromethyl group or -   a C₃₋₈-alkynyl group, -   X denotes an oxygen atom and -   R³ denotes a hydrogen atom, -   a C₁₋₂₀-alkyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 6 methylene     groups may each be replaced by an oxygen or sulphur atom or by an     —NH— or —N(C₁₋₃-alkyl)-group, -   a C₁₋₁₂-alkyl group substituted by a group R_(c) wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms     and wherein 1 to 4 methylene groups may each be replaced by an     oxygen or sulphur atom or by an —NH— or —N(C₁₋₃-alkyl)-group, and     where R_(c) is as hereinbefore defined, -   a C₃₋₈-cycloalkyl group wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms and wherein 1 to 4 methylene     groups may each be replaced by an oxygen or sulphur atom or by an     —NH— or —N(C₁₋₃-alkyl)-group, -   a C₃₋₂₀-alkenyl group or -   a C₃₋₂₀-alkynyl group, -   with the exclusion of the compound wherein R¹ denotes a bromine     atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³     denotes a methyl group, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

But particularly those compounds of general formula I, wherein

-   R¹ denotes a bromine atom, -   R² denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group, -   a 2-butyn-1-yl group or -   a 2-chlorophenylmethyl or 2-bromophenylmethyl group, -   X denotes an oxygen atom, and -   R³ denotes a C₁₋₁₀-alkyl group or C₃₋₈-cycloalkyl group, -   with the exclusion of the compound wherein R¹ denotes a bromine     atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³     denotes a methyl group, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

The following compounds of general formula I are particularly preferred:

-   (a) methyl     2-bromo-5-formyl-3-(3-methyl-2-buten-1-yl)-3H-imidazole-4-carboxylate     and -   (b) ethyl     2-bromo-5-formyl-3-(2-butyn-1-yl)-3H-imidazole-4-carboxylate and the     salts thereof.

According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:

a) Reduction of a Compound of General Formula

wherein

-   R¹ to R³ and X are as hereinbefore defined and Y denotes a     carboxylic acid, carboxylic acid amide, nitrile, carboxylic acid     ester, carboxylic acid thioester, carboxylic anhydride or carboxylic     acid chloride group, each bound to the imidazole ring via the     carboxyl carbon atom.

Reductions of the above-mentioned carboxylic acid derivatives to aldehydes are standard transformations in synthetic organic chemistry. A summary of the various possibilities can be found in Steven D. Burke, Rick L. Danheiser, Oxidizing and Reducing Agents, Weinheim: John Wiley, 1999 and in J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, Weinheim: VCH, 1991.

The following are a few representative examples:

Carboxylic acids may be converted into aldehydes, for example, with alkali metals such as lithium in ammonia or methylamine and subsequent hydrolysis of the resulting imine. Moreover, metal hydrides such as diisobutylaluminium hydride or boranes such as thexylchloro or bromoborane may be used. The reactions may be carried out at temperatures between −80° C. and 100° C., preferably between −70° C. and 40° C.

Carboxylic acid amides or nitriles may be reacted, e.g., with diisobutylaluminium hydride, lithium or sodium aluminium hydride, lithium tri-tert.-butoxyaluminium hydride and diaminoaluminium hydrides in solvents such as tetrahydrofuran, ether, toluene, hexane or dichloromethane to form the corresponding aldehydes. The reactions may be carried out at temperatures between −80° C. and 100° C., preferably between −70° C. and 25° C.

Of the examples of reducing agents which are able to convert carboxylic acid esters or anhydrides into aldehydes, hydride such as diisobutylaluminium hydride, diamino-aluminium hydride, lithium tri-tert.-butoxyaluminium hydride and sodium-bis(2-methoxyethoxy)aluminium hydride in solvents such as dichloromethane, toluene or hexane may be mentioned as being particularly suitable. The reactions may be carried out at temperatures between −80° C. and 100° C., preferably between −70° C. and 0° C.

Carboxylic acid thioesters may for example be converted into aldehydes by transition metals or transition metal complexes such as, e.g., palladium or nickel, in the presence of hydrides such as trialkylsilanes or molecular hydrogen. The use of metal hydrides such as diisobutylaluminium hydride in solvents such as hexane, dichloromethane or toluene is also a generally known method of reducing thioesters to aldehydes. The reactions may be carried out at temperatures between −80° C. and 100° C., preferably between −70° C. and 25° C.

Carboxylic acid chlorides may be converted, inter alia, with hydrogen in the presence of transition metals, such as, e.g., palladium on charcoal or barium sulphate, to form the corresponding aldehydes. Sodium borohydride in dimethylformamide and tetrahydrofuran or lithium tri-tert.-butoxyaluminium hydride in diglyme are equally suitable in many cases. The reactions may be carried out at temperatures between −100° C. and 100° C. In the presence of transition metal catalysts temperatures between 0° C. and 30° C. are preferred, whereas the reactions with metal hydrides are best carried out between −30° C. and −80° C.

b) Oxidation of a Compound of General Formula

wherein R¹, R², R³ and X are as hereinbefore defined.

The oxidation of a hydroxymethyl group to form an aldehyde is a standard reaction in synthetic organic chemistry. The oxidising agent used may be one of a number of reagents. A summary of oxidation methods and reagents for converting alcohols into aldehydes may be found in Steven D. Burke, Rick L. Danheiser, Oxidizing and Reducing Agents, Weinheim: John Wiley, 1999 and in Milos Hudlicky, Oxidation in Organic Chemistry, Washington: ACS, 1990.

Examples include:

Oxidation with dimethylsulphoxide in the presence of for example oxalyl chloride, acetic anhydride, or sulphur trioxide-pyridine complex. Very mild oxidation can be carried out with compounds of iodine at high oxidation stages such as in so-called Dess-Martin-Periodinane. Oxidation by dehydrogenation by means of a transition metal or transition metal salt, such as, e.g., copper oxide, palladium acetate or Raney nickel, is also possible. N-iodine, N-bromine, or N-chlorosuccinimide are similarly suitable oxidizing agents for the above-mentioned transformation. Oxidation with metals at high oxidation stages or the complexes and salts thereof, such as, e.g., manganese dioxide, barium manganate, pyridinium chlorochromate, pyridinium dichromate, potassium or sodium dichromate, cerium ammonium nitrate, silver carbonate, lead tetraacetate or tetrapropylammonium perruthenate are also widely useable. The metals may be used in stoichiometric amounts or in catalytic amounts when used in the presence of a suitable co-oxidant, such as for example N-methylmorpholine-N-oxide, sodium hypochloride or sodium bromate. The choice of solvent depends on the reagent, but in many cases tetrahydrofuran, ether, dioxane, toluene, hexane, dichloromethane, ethyl acetate, sulpholane or dimethylformamide are suitable. The reactions may be carried out at temperatures between −80° C. and 100° C. Preferably the reactions are carried out between 0° C. and 60° C.

Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known, per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971), into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known, per se, e.g., by chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by re-crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as, e.g., esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g., on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are, e.g., the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (−)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into the salts thereof. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid or formic acid.

In addition, if they contain a carboxy group, the new compounds of formula I thus obtained may, if desired, be converted into the salts thereof with inorganic or organic bases. Suitable bases include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

The compounds of general formulae II and III used as starting materials are either known from the literature or may be obtained by methods known from the literature (cf. Examples 1 and 2).

In addition to the process for preparing the compounds of general formula I the invention also relates to the use of the compounds of general formula I for synthesising imidazo[4,5-d]pyridazin-4-ones of general formula IV according to Diagram 1 and the overall process for preparing imidazo[4,5-d]pyridazin-4-ones of general formula IV starting from commercially obtainable imidazole derivatives. The access to compounds of general formula I described here combined with their further reaction with hydrazines results in an extremely efficient and variable method of synthesising imidazo[4,5-d]pyridazin-4-ones of type V (Diagram 2), which are very good inhibitors of dipeptidylpeptidase IV (DPP IV) and can be used to treat diabetes. The method described makes it possible to obtain a wide and efficient variation in the substituents R¹, R² and R⁴ of the imidazo[4,5-d]pyridazin-4-ones, making it possible to optimise all the substituents in the light of particular biological activities which are desirable or undesirable. The option of varying R¹ and R⁴ at a late stage of the synthesis sequence constitutes a significant advantage over the methods described in WO 03/104229, according to which only R⁴ can be varied at a late stage of the synthesis. The synthesis of a particular imidazo[4,5-d]pyridazin-4-one, such as, e.g., the one shown in Diagram 2, can be achieved in the manner described above in only four or five synthesis steps starting from the dimethyl 2-bromo-1H-imidazole-4,5-dicarboxylate known from the literature. In this respect, too, the method of synthesis described constitutes a significant improvement over the method of synthesis described in WO 03/104229, which would yield the same compound in nine or ten reaction steps starting from the 2-bromo-1H-imidazole-4,5-dicarboxylic acid nitrile known from the literature.

Diagram 1: Synthesis of imidazo[4,5-d]pyridazin-4-ones (IV) starting from Compounds of General Formula I

Diagram 1 shows a process for preparing imidazo[4,5-d]pyridazin-4-ones of general formula IV, wherein R¹ and R² are as hereinbefore defined, starting from the compound of general formula I wherein R¹ to R³ and X are as hereinbefore defined, and a hydrazine substituted by R⁴, where

-   R⁴ may denote for example a hydrogen atom, -   a C₃₋₈-alkyl group, -   a C₁₋₃-alkyl group substituted by a group R_(a), while R_(a) is as     hereinbefore defined, -   a C₃₋₈-alkenyl or C₃₋₈-alkynyl group, -   an arylcarbonylmethyl or heteroarylcarbonylmethyl group, -   an arylprop-2-enyl or heteroarylprop-2-enyl group or -   an aryl group or heteroaryl group.

The compounds of formula IV may be synthesised by reacting compound I with a hydrazine substituted by R⁴ or a protected hydrazine derivative thereof, such as, e.g., 1,2-bis-(t-butyldimethylsilyl)hydrazine, in a solvent such as, e.g., water, an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, ether, dioxane, tetrahydrofuran, dimethylsulphoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, ethyl acetate, benzene or toluene. The addition of additives such as acids or bases may promote the reaction depending on X. Suitable organic acids include, e.g., toluenesulphonic acid, formic acid, acetic acid, oxalic acid or citric acid. Examples of inorganic acids which may be used are hydrochloric acid, boric acid, or sulphuric acid. Acidic clays such as, e.g., montmorillonite or Lewis acids such as for example iron chloride, lithium chloride, lithium perchlorate or magnesium chloride may also be used. Suitable inorganic bases are, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, aluminium oxide or sodium acetate. Organic bases such as, e.g., triethylamine, diisopropylethylamine, diazabicycloundecane, diazabicyclononane, diazabicyclooctane, pyridine, dimethylaminopyridine, N-methyl-piperidine or hexamethyldisilazane may also be suitable. It is also possible to carry out reactions in the corresponding additive without any additional solvent. The reactions may be carried out at temperatures between −80° C. and 200° C., preferably between 0° C. and 120° C. The reactions may also be carried out under microwave radiation.

The imidazo[4,5-d]pyridazin-4-ones thus obtained may be converted by suitable substitution using methods known, per se, for example, into good inhibitors of dipeptidylpeptidase IV (DPP IV), which may in turn be used in the treatment of diabetes. Diagram 2 shows, by means of an example, the synthesis of such a compound starting from a compound of general formula I.

Compounds of general formula I may be used for efficiently synthesising imidazo[4,5-d]pyridazin-4-ones of general formula IV. By suitable substitution, good DPPIV inhibitors may be obtained therefrom, as shown by the example in Diagram 2.

Diagram 2: Synthesis of a DPP IV Inhibitor Starting from a Compound of General Formula I

The synthesis sequence begins with the reaction of VI, which is concrete example of a compound of general formula I, with hydrazine hydrate in ethanol. After total reaction of VI with hydrazine to form the hydrazone, acetic acid is added and the solution is stirred at 100° C. Then VII is obtained in a high yield. Alkylation of VII with 2-(chloromethyl)-4-methylquinazoline IX in the presence of potassium carbonate in DMF produces X. Alternatively X may also be synthesised directly from VI with 2-(hydrazinylmethyl)-4-methyl-quinazoline VIII. This is done in the same way as from VI to VII. X is then reacted with (R)-3-t-butyloxycarbonylamino-piperidine in DMSO at 70° C. to produce XI, which is then obtained in a good yield. In the final reaction step the protective group in XI, t-butyloxycarbonyl, is cleaved under acidic conditions, e.g., with trifluoroacetic acid or alcoholic hydrochloric acid in dichloromethane. The DPP IV inhibitor V is thus obtained in only three or four reaction steps in consistently high yields.

The Examples that follow are intended to illustrate the invention more fully:

EXAMPLE 1 Methyl 2-bromo-3-(3-methyl-2-buten-1-yl)-5-formyl-3H-imidazole-4-carboxylate

1a) dimethyl 2-bromo-1H-imidazole-4,5-dicarboxylate

At ambient temperature 9.50 g (59.45 mmol) bromine were added dropwise to a solution of 9.90 g (53.76 mmol) dimethyl imidazole-4,5-dicarboxylate in 300 ml dichloromethane and 80 ml acetonitrile. 7.46 g (54.00 mmol) potassium carbonate was added, and the reaction mixture was stirred for 2 hours at ambient temperature. Then the dichloromethane was eliminated using the rotary evaporator and the residue was combined with a saturated solution of sodium chloride and sodium thiosulphate. It was extracted ten times with ethyl acetate, the organic extracts were dried over sodium sulphate and then the solvent was eliminated.

-   Yield: 12.31 g (87% of theory) -   C₇H₇BrN₂O₄ (263.05) -   Mass spectrum: (M+H)⁺=263/265 (bromine)

1b) dimethyl 2-bromo-1-(3-methyl-2-buten-1-yl)-1H-imidazole-4,5-dicarboxylate

A mixture of 12.20 g (46 mmol) dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 7.16 g (48 mmol) 1-bromo-3-methyl-2-butene and 7.19 g (52 mmol) potassium carbonate in 150 ml of dimethylformamide were stirred for two hours at 50° C. Then 100 ml of water were added, and the mixture was extracted three times with ethyl acetate. The extracts were dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant: cyclohexane/ethyl acetate 4:1->2:1).

-   Yield: 13.52 g (89% of theory) -   C₁₂H₁₅BrN₂O₄ (331.16) -   Mass spectrum: (M+H)⁺=331/333 (bromine)

1c) methyl 2-bromo-3-(3-methyl-2-buten-1-yl)-5-formyl-3H-imidazole-4-carboxylate

Under an argon atmosphere 35 ml (35 mmol) diisobutylaluminium hydride (1 mol/l in toluene) were added dropwise at −65° C. within 20 minutes to a solution of 9.00 g (12.18 mmol) dimethyl 2-bromo-1-(3-methyl-2-buten-1-yl)-1H-imidazole-4,5-dicarboxylate in 140 ml of tetrahydrofuran. After 1 hour at −65° C. another 5 ml (5 mmol) diisobutylaluminium hydride (1 mol/l in toluene) was added dropwise. The mixture was stirred for a further hour at −65° C. and then 20 ml of a 1:1 mixture of hydrochloric acid (1 mol/l) and tetrahydrofuran were added dropwise. After heating to ambient temperature approx. 100 ml of water was added, and the mixture was extracted three times with 70 ml of ethyl acetate. The extracts were dried over sodium sulphate, evaporated down, and the crude product thus obtained was purified by column chromatography (silica gel; eluant: cyclohexane/ethyl acetate 3:1->1:2).

-   Yield: 7.03 g (86% of theory) -   C₁₁H₁₃BrN₂O₃ (301.14) -   Mass spectrum: (M+H)⁺=301/303 (bromine)

EXAMPLE 2 Ethyl 2-bromo-3-(but-2-ynyl)-5-formyl-3H-imidazole-4-carboxylate

2a) diethyl 2-bromo-1H-imidazole-4,5-dicarboxylate

Under an argon atmosphere 3.30 g (18.54 mmol) N-bromosuccinimide were added to a solution of 2.60 g (12.25 mmol) diethyl imidazole-4,5-dicarboxylate in 30 ml acetonitrile. The solution was stirred for 24 hours in the dark at ambient temperature and then evaporated down. The residue was taken up in 150 ml of ethyl acetate and washed twice each with saturated aqueous sodium chloride solution and saturated aqueous sodium thiosulphate and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and the solvent was removed.

-   Yield: 3.50 g (98% of theory) -   C₉H₁₁BrN₂O₄ (291.10) -   Rf value: 0.6 (silica gel; dichloromethane/ethanol 9:1) -   Mass spectrum: (M+H)⁺=291/293 (bromine)

2b) diethyl 2-bromo-1-(but-2-ynyl)-1H-imidazole-4,5-dicarboxylate

Prepared analogously to 1b from 3.50 g (12.02 mmol) diethyl 2-bromo-imidazole-4,5-dicarboxylate with 1.09 ml (12.1 mmol) 1-bromo-2-butyne and 2.07 g (15.00 mmol) potassium carbonate in 15 ml of dimethylformamide.

-   Yield: 3.60 g (87% of theory) -   C₁₃H₁₅BrN₂O₄ (343.17) -   Rf value: 0.8 (silica gel; dichloromethane/ethanol 9:1) -   Mass spectrum: (M+H)⁺=343/345 (bromine)

2c) ethyl 2-bromo-3-(but-2-ynyl)-5-formyl-3H-imidazole-4-carboxylate

Prepared analogously to 1c from 20.00 g (58.28 mmol) diethyl 2-bromo-1-(but-2-ynyl)-1H-imidazole-4,5-dicarboxylate with 70 ml (70 mmol) diisobutylaluminium hydride in 300 ml of tetrahydrofuran.

-   Yield: 15.90 g (91% of theory) -   C₁₁H₁₁BrN₂O₃ (299.12) -   Mass spectrum: (M+H)⁺=299/301 (bromine)

The following compounds may be prepared analogously to the foregoing Examples and other methods known from the literature:

Ex. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

EXAMPLE 3 a) 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (VII)

6.31 ml (0.126 mol) hydrazine hydrate were added drop-wise at ambient temperature to a solution of 35.0 g (0.117 mol) ethyl 2-bromo-3-(but-2-ynyl)-5-formyl-3H-imidazole-4-carboxylate in 400 ml of ethanol. After 30 min stirring 27 ml (0.472 mol) concentrated acetic acid were added and the solution was then stirred for 1 h at 100° C. After cooling the precipitated solid was suction filtered, washed with ethanol and diethyl ether and dried. The solid was further purified by re-crystallization from EtOH.

-   Yield: 84% of theory. -   C₉H₇BrN₄O (267.09) -   Mass spectrum: (M+H)⁺=267/269 (Br)

b) 2-bromo-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (X)

489 mg (1.5 mol) cesium carbonate were added to a solution of 300 mg (1.12 mmol) 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 344 mg (1.35 mmol) 2-chloromethyl-4-methyl-quinazoline in 4 ml of dimethylformamide and this mixture was stirred for 1 h under an argon atmosphere at 80° C. Then the mixture was diluted with 10 ml of water, the solution was cooled to approx. 10° C., the precipitate formed was suction filtered and dried and purified by column chromatography (silica gel; eluant: dichloromethane/ethanol 1:0->19:1).

-   Yield: 94% of theory. -   C₁₉H₁₅BrN₆O (423.28) -   Mass spectrum: (M+H)⁺=423/425 (Br)

c) tert-butyl (R)-{1-[1-(but-2-ynyl)-6-(4-methyl-quinazolin-2-ylmethyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]-piperidin-3-yl}-carbamate (XI)

A solution of 240 mg (0.57 mmol) 2-bromo-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 140 mg (0.70 mmol) tert-butyl (R)-piperidin-3-yl-carbamate in 4 ml dimethylsulphoxide was combined with 95 mg (0.90 mmol) sodium carbonate and stirred for 3 h at 80° C. Then another 50 mg tert-butyl piperidin-3-yl-carbamate was added and the mixture was stirred for a further 2 h at 80° C. After cooling to ambient temperature the mixture was combined with 10 ml of water and stirred for 30 minutes. The product thus precipitated was suction filtered, washed with 5 ml of water and dried.

-   Yield: 81% of theory. -   C₂₉H₃₄N₈O₃ (542.65) -   Mass spectrum: (M+H)⁺=543

d) (R)-2-(-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (V)

A solution of 17.2 g (31.7 mmol) tert-butyl (R)-{1-[1-(but-2-ynyl)-6-(4-methyl-quinazolin-2-ylmethyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]-piperidin-3-yl}-carbamate in 400 ml dichloromethane was combined with 85 ml trifluoroacetic acid and stirred for three hours at ambient temperature. The mixture was evaporated to dryness at 30° C., the residue was dissolved in dichloromethane and the solution was made basic with ice-cooled saturated sodium carbonate solution. The organic phase was separated off and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were dried over sodium sulphate and the solvent was removed. The residue was purified by chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 95:5:0.1).

-   Yield: 89% of theory. -   C₂₄H₂₆N₈O (442.53) -   Mass spectrum: (M+H)⁺=443

The following compounds were obtained analogously to Example 3:

Ex. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14) 

1. A compound of formula (I):

wherein R¹ denotes a fluorine, chlorine, bromine or iodine atom, R² denotes a C₃₋₈-alkyl group, or a C₁₋₃-alkyl group substituted by a group R_(a), while R_(a) denotes: a C₃₋₇-cycloalkyl group optionally substituted by one or two C₁₋₃-alkyl groups, a C₃₋₈-cycloalkenyl group optionally substituted by one or two C₁₋₃-alkyl groups, an aryl group or a heteroaryl group, a C₃₋₈-alkenyl group, a C₃₋₆-alkenyl group substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl group, a C₃₋₈-alkynyl group, an aryl group or an aryl-C₂₋₄-alkenyl group, X denotes an oxygen or sulphur atom or a nitrogen atom which is substituted by R_(b), while R_(b) denotes: a hydrogen atom, a hydroxy, aryloxy, arylmethyloxy, heteroaryloxy, heteroarylmethyloxy or C₁₋₁₀-alkyloxy group, while the hydrogen atoms of the alkyloxy group may be wholly or partly replaced by fluorine atoms, a C₁₋₁₀-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C₁₋₁₀-alkyloxy-carbonyl, C₁₋₁₀-alkylaminocarbonyl, di-(C₁₋₁₀-alkyl)-aminocarbonyl, C₁₋₁₀-alkylsulphonyl, arylsulphonyl, heteroarylsulphonyl, C₁₋₁₀-alkylsulphinyl, arylsulphinyl or heteroarylsulphinyl group, while the hydrogen atoms of the above-mentioned C₁₋₁₀-alkyl groups may be wholly or partly replaced by fluorine atoms, a C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₇-cycloalkyl or C₅₋₈-cycloalkenyl group, while the hydrogen atoms in the above-mentioned groups may each be wholly or partly replaced by fluorine atoms and in the above-mentioned groups 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, an aryl group or a heteroaryl group, or R_(b) and R³ are linked together and are closed up into a ring at the nitrogen atom, while R_(b) and R³ together denote: a C₂₋₇-alkylene group, while one or two methylene groups may each be substituted by one or two fluorine atoms or replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, or a C₄₋₇-alkenylene group, while one or two methylene groups may each be substituted by one or two fluorine atoms or replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group and the double bond may be part of an aryl or heteroaryl group anellated to the ring, and R³ denotes: a hydrogen atom, a C₁₋₂₀-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₁₋₁₂-alkyl group substituted by a group R_(c) wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, while R_(c) denotes: a C₃₋₁₈-cycloalkyl group optionally substituted by one or two C₁₋₃-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein one to two methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₅₋₁₈-cycloalkenyl optionally substituted by: one or two C₁₋₃-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, one to two methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group and the double bond may be part of an aryl or heteroaryl group anellated to the ring; an aryl group or a heteroaryl group, a C₃₋₁₈-cycloalkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₃₋₂₀-alkenyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₅₋₂₀-cycloalkenyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, and wherein the double bond may be part of an aryl or heteroaryl group anellated to the ring, a C₃₋₂₀-alkynyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, an aryl group, a heteroaryl group, an aryl-C₂₋₆-alkenyl group or, if X does not represent a nitrogen atom which is substituted by a hydroxy, aryloxy, arylmethyloxy, heteroaryloxy, heteroarylmethyloxy or C₁₋₁₀-alkyloxy group, R³ may also denote an amino group which may be substituted by one or two C₁₋₃-alkyl groups, or, if X does not represent a nitrogen atom which is substituted by a hydroxy, aryloxy, arylmethyloxy, heteroaryloxy, heteroarylmethyloxy or C₁₋₁₀-alkyloxy group, R³ may also denote a 3- to 7-membered cycloalkyleneimino group, while one to two methylene groups of the cycloalkyleneimino group may each be replaced by an oxygen atom or a carbonyl, sulphinyl or sulphonyl group, or R³ and X together represent a fluorine or chlorine atom, while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which may be mono- to pentasubstituted independently of one another by fluorine and chlorine atoms and may be mono-, di- or trisubstituted by R_(d), while the substituents may be identical or different and R_(d) denotes a bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, aminosulphonyl, methylsulphonyl, acetylamino, methylsulphonylamino, C₁₋₄-alkyl, C₁₋₃-alkyl-carbonyl, cyclopropyl, ethenyl, ethynyl, hydroxy, C₁₋₄-alkyloxy, C₁₋₄-alkoxy-carbonyl, methylsulphinyl, phenylsulphinyl, methylsulphonyl, phenylsulphonyl, difluoromethoxy or trifluoromethoxy group, by the heteroaryl groups mentioned in the definition of the above-mentioned groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group or a pyrrolyl, furanyl, thienyl or pyridyl group wherein one or two methyne groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group wherein one to three methyne groups are replaced by nitrogen atoms, and the above-mentioned heteroaryl groups may be mono- to pentasubstituted by fluorine and chlorine atoms and R_(d) may be mono-, di- or trisubstituted, while the substituents may be identical or different and R_(d) is as hereinbefore defined, by the cycloalkyl groups mentioned in the above definitions are meant both mono- and polycyclic ring systems, which are either bridged, spiro-bridged or anellated in construction, by the cycloalkenyl groups mentioned in the above definitions are meant both mono- and polycyclic ring systems, which are either bridged or anellated in construction, and have at least one C═C double bond, while, unless otherwise stated, the above-mentioned alkyl, alkenyl and alkynyl groups may be straight-chain or branched, with the exclusion of the compound wherein R¹ denotes a bromine atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³ denotes a methyl group, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
 2. The compound of formula (I) according to claim 1, wherein R² and R³ are defined as in claim 1, R¹ denotes a chlorine or bromine atom and X denotes an oxygen atom or an —NH— or —N(C₁₋₃-alkyl)-group, with the exclusion of the compound wherein R¹ denotes a bromine atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³ denotes a methyl group, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
 3. The compound of formula (I) according to claim 2, wherein R¹ denotes a chlorine or bromine atom, R² denotes a C₁₋₃-alkyl group substituted by a group R_(a), where R_(a) is as hereinbefore defined, a C₃₋₈-alkenyl group, a C₃₋₆-alkenyl group substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl group or a C₃₋₈-alkynyl group, X denotes an oxygen atom and R³ denotes a hydrogen atom, a C₁₋₂₀-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₁₋₁₂-alkyl group substituted by a group R_(c) wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, where R_(c) is as hereinbefore defined, a C₃₋₈-cycloalkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₃₋₂₀-alkenyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, a C₃₋₂₀-alkynyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom, by an —NH— or —N(C₁₋₃-alkyl)-group or by a carbonyl, sulphinyl or sulphonyl group, or an aryl-C₂₋₆-alkenyl group, with the exclusion of the compound wherein R¹ denotes a bromine atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³ denotes a methyl group, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
 4. The compounds of formula (I) according to claim 3, wherein R¹ denotes a chlorine or bromine atom, R² denotes a phenylmethyl group which may be substituted at the phenyl ring by a fluorine, chlorine, bromine or iodine atom or by a cyano or methoxy group, a C₃₋₈-alkenyl group, a C₃₋₈-cycloalkenylmethyl group, a C₃₋₆-alkenyl group substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl group or a C₃₋₈-alkynyl group, X denotes an oxygen atom and R³ denotes a hydrogen atom, a C₁₋₂₀-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 6 methylene groups may each be replaced by an oxygen or sulphur atom or by an —NH— or —N(C₁₋₃-alkyl)-group, a C₁₋₁₂-alkyl group substituted by a group R_(c) wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom or by an —NH— or —N(C₁₋₃-alkyl)-group, and where R_(c) is as hereinbefore defined, a C₃₋₈-cycloalkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms and wherein 1 to 4 methylene groups may each be replaced by an oxygen or sulphur atom or by an —NH— or —N(C₁₋₃-alkyl)-group, a C₃₋₂₀-alkenyl group or a C₃₋₂₀-alkynyl group, with the exclusion of the compound wherein R¹ denotes a bromine atom, R² denotes a 2-butynyl group, X denotes an oxygen atom and R³ denotes a methyl group, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
 5. The compound of formula (I) according to claim 4, wherein R¹ denotes a bromine atom, R² denotes a 2-buten-1-yl or 3-methyl-2-buten-1-yl group, a 2-butyn-1-yl group, or a 2-chlorophenylmethyl or 2-bromophenylmethyl group, X denotes an oxygen atom, and R³ denotes a C₁₋₁₀-alkyl group or C₃₋₈-cycloalkyl group, with the exclusion of the compound wherein R¹ denotes a bromine atom, R² denotes a 2-butynyl group, X denotes an oxygen atom, and R³ denotes a methyl group, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.
 6. The compound of formula (I) according to claim 5 wherein the compound is: (a) methyl 2-bromo-5-formyl-3-(3-methyl-2-buten-1-yl)-3H-imidazole-4-carboxylate, (b) ethyl 2-bromo-5-formyl-3-(2-butyn-1-yl)-3H-imidazole-4-carboxylate and the salts thereof.
 7. A process for preparing a compound of formula (I) according to claim 1, comprising: a) reducing a compound of formula (II):

 wherein R¹ to R³ and X are defined as in claim 1 and Y denotes a carboxylic acid, carboxylic acid amide, nitrile, carboxylic acid ester, carboxylic acid thioester, carboxylic anhydride or carboxylic acid chloride group, each of which is bound to the imidazole ring via the carboxyl carbon atom, or b) oxidizing a compound of formula(III):

 wherein R¹, R², R³ and X are defined as mentioned in claim
 1. 